First-of-its-kind preventative phage therapy provides promising results

Virginia Tech

Facebook

XLinkedIn
MessageWhatsAppEmail

image: 

(From left) Roger Bataglioli and Hiba Baaziz in the lab.

view more 

Credit: Photo by Felicia Spencer for Virginia Tech.

The mammalian gut microbiome is teeming with a delicate balance of bacteria and the viruses that keep them in check, called bacteriophages, or phages. Each bacterial species usually has its own set of phage partners. 

When bad bacteria enter this ecosystem, there are typically no phages present, allowing them to cause mayhem. By the time the host is sick, it is too late for phages; they’ll simply reach a balance with the bad bacteria.

But what if the phages in the gut could prepare for the orally ingested pathogen and strike it down as it enters the gut, negating the need for a battle?

Associate Professor and Blackwood Junior Faculty Fellow Bryan Hsu and his team recently demonstrated that this prophylactic approach, using an engineered nonpathogenic E. coli bacterium, successfully protected mice from an oral salmonella infection. Their work was published in Nature Microbiology.

The team believes this is a step toward an additional weapon against illnesses. 

“Eventually, in the future, this could be used to treat other diseases,” said Rogerio A. Bataglioli, a postdoctoral fellow in the Department of Biological Sciences and lead author of the study. “It’s not about replacing antibiotics but having one more option on the shelf to fight infections.” 

Bacteriophages, or phages, are viruses of bacteria and do not infect humans or animals. Hsu said phage therapy, the use of phages to treat bacterial infections, is particularly hard to make successful for treating intestinal pathogens. 

“It’s challenging, especially in the gut, because phages and bacteria tend to coexist for long periods of time,” said Hsu, an affiliate with Fralin Life Sciences Institute’s Center for Emerging, Zoonotic, Arthropod-borne Pathogens.  

This coexistence makes establishing the high phage-to-bacteria ratio needed to treat intestinal infections hard to achieve. 

“That’s extremely challenging to achieve in your gut,” Hsu said. “And then once you have a bacterial infection in your gut, a lot of times it’s just not even accessible to phages. It’s already hidden away in the mucosa or cells of your body; it’s not just free-flowing to where the phages would be able to access them.”  

To work around these impediments, the team engineered a nonpathogenic E. coli bacterium to carry a phage that only infects salmonella. This ensures that when the phage is produced, it can specifically target the pathogen.   

Usually, this type of salmonella phage remains dormant in the salmonella bacterial genome, but Hsu’s team made several genetic modifications so that it is carried by E. coli, and, once it is released into the gut, it automatically kills salmonella in a process called lysis. This process rapidly increases the number of phages to fight the bacteria. The researchers coined this new type of phage-bacterial combination a “lytic phage-producing lysogen,” or “lyto-lysogen.”

Salmonella can typically detect phage DNA produced by non-salmonella bacteria and prevent it from replicating. But in this case, the researchers were able to disguise the phage.

“We were able to trick the salmonella bacteria into thinking the phage from E. coli was ‘not foreign’ by adding a salmonella gene into the E. coli genome,” Bataglioli said. “A phage that comes from our E. coli can infect salmonella, can propagate easily in salmonella, lyse it, and then all the phages that are produced from salmonella can just keep replicating.” 

This rapid reproduction eventually leads to the eradication of the infection from the gut. 

“What happens is that this good bacteria, the E. coli, produces all this antipathogen phage, and there is now a protective lining so that when salmonella comes in, just after passing through the stomach and at its weakest point, it meets this high, killer density of phages,” Hsu said.  

The researchers say they targeted salmonella due to its high global disease burden, as it can kill the elderly, children, and those with HIV; it has a high prevalence of antibiotic resistance; and it has been upgraded to a high-priority pathogen by the Centers for Disease Control and Prevention. They believe this work, however, has strong implications for other illnesses. 

“We’re starting off with salmonella, but expanding, obviously, with the correct adaptations to target other diseases; other bacterial pathogens, would be an interesting route to explore,” Bataglioli said. 

“We have a framework in place that shows that we could potentially put other phages in there and target other bacteria,” Hsu said. 

Bataglioli plans to continue his bacteriophage research with the School of Chemical Engineering at the State University of Campinas in São Paulo, Brazil, in the fall.

Funding for this research was provided by the National Institute of General Medical Sciences of the National Institutes of Health. Bataglioli’s funding was supported by the Postdoctoral Fellowship in Drug Delivery from the PhRMA Foundation. 

Other researchers involved in this study include the following: 

• Hiba Baaziz, Ph.D., lab manager, biological sciences 

• Hallie Avalos, currently a graduate student at Vanderbilt University Medical Center 

• Lindsay Smith, undergraduate researcher, College of Science 

• Zach Baker, Ph.D., current postdoctoral researcher at Colgate-Palmolive 

• Rita Makhlouf, graduate student, biological sciences

• David Da Silva Barreira, Ph.D., current postdoctoral researcher at the University of Wisconsin, Madison 

• Harsimran Kaur, Ph.D., presidential postdoctoral associate in biological sciences 

• Teresa Southard, associate professor at the Virginia-Maryland College of Veterinary Medicine

---

Journal

Nature Microbiology

DOI

10.1038/s41564-026-02484-3

Article Publication Date

16-Sep-2026

 

Micro-bladder model offers clues to stopping recurrent UTIs

University College London

Facebook

XLinkedInWeChatBlueskyMessageWhatsAppEmail

 

image: 

Senior author Professor Jennifer Rohn (UCL Division of Medicine) pipetting in her laboratory.

view more 

Credit: Jennifer Rohn.

The study, published in Nature Communications, shows that phage therapy – the use of tiny viruses to kill bacteria without harming people – could help to reduce recurrent infections, which happen when the bacteria responsible for UTIs ‘hide’ in the tissue of the bladder.

UTIs are one of the world’s most common infections, with around 400 million cases each year. They can be painful and disruptive, and for many people the infection can return after taking a course of antibiotics.

The researchers sought to understand why this happens by engineering a novel human 3D micro-bladder model that includes flowing urine to mimic the environment found in the human bladder.

The study, conducted as part of the larger Beyond Antibiotics Programme Grant and funded by the Engineering and Physical Science Research Council (EPSRC), used this bladder model to test phage therapy on UTI bacteria. The team found that this therapy can wipe out bacteria hidden deep within the bladder wall, in what the researchers label ‘reservoirs’, which normal antibiotics can’t touch.

Senior author of the study, Professor Jennifer Rohn (UCL Division of Medicine), said: “Recurrent UTIs are incredibly frustrating for patients because the bacteria can survive antibiotics by retreating into protected reservoirs inside the bladder wall.

“Building a micro-bladder has allowed us to mimic real conditions in the urinary tract and see why antibiotics that look powerful in standard lab tests often fall short.”

The team focused on uropathogenic Escherichia coli (UPEC), a strain of E. coli adapted to infect the urinary tract and the cause of most UTIs. In hospitals, bacteria from a patient’s urine can be tested to see which antibiotics stop them growing, but these tests are usually done in a still, nutrient-rich liquid.

A real bladder behaves differently: urine is constantly moving and the bacteria are interacting with the bladder lining.

Realistic bladder models are hard to run with routine laboratory protocols as they can be highly complex. To solve this, Dr Ramon Garcia Maset and colleagues at the University of Oxford developed a device that can work with typical cell cultures to recreate the flow conditions of urinary cycles.

When introducing UPEC to the micro-bladder, scientists found the bacteria became better at sticking to the bladder surface, and more likely to invade the bladder lining and set up protected reservoirs of bacteria hidden inside bladder cells where they are harder to reach.

The team then tested nitrofurantoin (a commonly used antibiotic for UTIs). In standard lab tests this treatment works well, but in the micro-bladder it struggled to fully clear the infection.

The researchers also tested a cocktail of phages, or viruses that infect and destroy bacteria. On its own, the phage cocktail also found it difficult to clear bacteria in a flowing environment. However, when the scientists combined phages with the antibiotic, the results improved, suggesting that a two-pronged approach could be more effective than either treatment alone.

One significant finding was that unlike the antibiotics, the phage treatment was able to reduce the number of protected bacterial reservoirs inside the bladder wall. Because these reservoirs can act like a breeding ground for future infection, reducing them could be an important step towards preventing UTIs from repeatedly returning.

Lead author Dr Garcia Maset said: “What’s particularly promising is that phage therapy was able to reach these hidden reservoirs of bacteria, rooting out the cause of the infection.

“We also discovered that urine flow substantially changes how bacteria behave and respond to treatment, suggesting that many conventional laboratory tests may be missing important aspects of the infection process.”

The study presented another potential benefit: phages appeared to boost the bladder tissue’s own early defence response. Researchers saw signs of increased immune signalling, including cytokines and chemokines (messenger proteins that help the body coordinate inflammation and bring immune cells to the site of infection).

Professor Martha Clokie, Director of the Becky Mayer Centre for Phage Research at the University of Leicester, said: “This study shows why it is so important to test phages under conditions that genuinely reflect the human body.

“By combining a realistic flowing micro-bladder model with phage and antibiotic treatment, we can begin to understand how best to use phages alongside existing medicines to achieve better outcomes for patients.”

Phage therapy is not yet a routine treatment for UTIs, and more research will be needed to confirm how well it works, how best to deliver it, and which patients are most likely to benefit. However, this study offers a promising route towards longer-lasting relief for people living with repeat UTIs.

The device design and image-analysis tools used in this study have been made freely available to encourage broader adoption across laboratories, with the hope they could find wider application in research focusing on the impact of flow-mediated mechanostimulation on biological systems.

---

Journal

Nature Communications

DOI

10.1038/s41467-026-76589-y 

Method of Research

Experimental study

Subject of Research

Cells

Article Title

Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli

Article Publication Date

4-Sep-2026

 

A viral 'loose cannon' enzyme helps phages shut down bacterial defenses

Scientists have found how phages, viruses that infect bacteria, orchestrate an explosion of protein modifications inside host cells that helps them evade the bacteria’s immune systems

European Molecular Biology Laboratory

Facebook

XLinkedInWeChatBlueskyMessageWhatsAppEmail

 

image: 

Illustration depicting how T7 kinase, a phage enzyme, modifies many proteins inside an infected bacterium, helping shut down its defence mechanisms.

view more 

Credit: Daniela Velasco/EMBL

Scientists have discovered a previously unknown strategy that phages – viruses that infect bacteria – use to disable bacterial defence systems. The strategy relies on T7 kinase, a phage enzyme that sets off an explosion of protein modifications inside infected bacteria, shutting down their defence systems.

Like all viruses, phages exist in a perpetual molecular arms race with their hosts. Bacteria evolve mechanisms to defend against infecting phages, while phages evolve anti-defence systems to shut down or evade these immune mechanisms. The new study demonstrates, for the first time, how a single phage protein can set off a wave of molecular events that can disarm multiple bacterial defences. 

These findings resulted from a long-standing collaboration between two research groups at EMBL Heidelberg – the Typas Group, which specialises in high-throughput studies of bacterial interactions, and the Savitski Team, who are experts in cutting-edge proteomics technologies. 

“Phage research has led to a lot of exciting developments, the CRISPR-Cas9 gene editing system among them,” said Mikhail Savitski, Senior Scientist and Head of Proteomics Core Facility at EMBL Heidelberg. “Using the sensitive technologies we had available in the lab, we wanted to understand in an unbiased way how phages affect bacterial proteins during infection.”

A loose cannon inside the cell

For this, the researchers used a well-known model system – E. coli, a rod-shaped bacterium that lives in our guts, and T7 phage, a virus that infects E. coli. The team decided to look closely at protein phosphorylation in phage-infected bacteria. Phosphorylation is a kind of rapid chemical modification of proteins which can change their function, e.g. by activating or inactivating them. 

Surprisingly, the scientists found that phage infection resulted in almost every single bacterial protein getting phosphorylated within minutes, at least for a fraction of their population within the cell. The likely culprit was T7 kinase, a phage enzyme first discovered in the 1970s. However, the scale of phosphorylation was unlike anything previously observed. In fact, the list of phosphorylation targets for the T7 kinase surpassed what’s known so far for any kinase in nature, leading the researchers to dub it a ‘loose cannon’. 

“We realised that we were seeing a quite unprecedented molecular event: a catastrophic phosphorylation across the entire proteome in a completely nonspecific manner,” said Savitski. “That had never been seen before, and it was fascinating that there was also no pattern to it.”

Shutting down bacterial defences

However, this discovery posed a new question. Previous studies had shown that deleting T7 kinase from the phage’s DNA doesn’t really affect the infection process. “As puzzles go, it leaves you a bit flabbergasted,” said Savitski. “You have a kinase with apparently no phenotype that seems to phosphorylate everything in the proteome.”

The researchers confirmed that the activity of the T7 kinase was short-lived – as previously reported, it inactivates itself within 5-6 minutes post infection. Examining the structure of T7 kinase yielded another important clue: one section of the kinase, called the shutoff domain, was not needed for its phosphorylation activity but was rich in chemical features that might help it bind DNA. This led the team to hypothesise that this domain might help the kinase attach to DNA and subsequently come close to other DNA-binding proteins.

“Methodologically, it is not easy to test such things, but we designed an elegant experiment that could measure exactly how much of a protein population is phosphorylated inside a cell,” said Tara Bartolec, postdoc at EMBL Heidelberg and one of the first authors of the paper. Using this, the researchers found that the T7 kinase preferentially targeted DNA-binding bacterial proteins, phosphorylating and presumably inactivating them.

DNA-binding proteins are often the bedrock of bacterial defence systems, helping them detect and destroy phage DNA inside the cell. And indeed, the researchers found that the kinase could help the virus infect strains of bacteria that had such defence systems. 

By also comparing kinases across different types of phages, the researchers believe they may have hit upon an evolutionarily conserved mechanism that certain phages use to deactivate bacterial immune systems.

In the future, the researchers plan to look at other protein modifications and the role they might play in phage infections. The study also opens up the possibility of novel bioengineering approaches that use these new insights into phage biology to design or predict the effectiveness of phage therapies.

”To be effective for therapy, phages should be capable of infecting diverse versions (strains) of the same pathogen,” said Typas. “Interestingly, pathogenic strains are exquisitely diverse in their immune repertoire, and can always pick up new systems. So engineering phages with broad anti-defence systems, such as the T7 kinase, might be key in this quest for effective phage therapies. We identified the first one here, but we are sure there are many more out there.”

---

Journal

Nature

DOI

10.1038/s41586-026-10934-5 

Article Title

Pervasive phosphorylation by phage T7 kinase disarms bacterial defenses

Article Publication Date

19-Aug-2026

 

Mutation hotspots help 'friendly' viruses outmaneuver the bacteria in your gut

Could we harness their chameleon-like nature to treat infections when antibiotics don’t work?

Michigan State University

Facebook

X
BlueskyMessageWhatsAppEmail

 

image: 

Certain bacteriophages found in the human gut have mutation hotspots scattered throughout their genomes that help them modify key defense genes, researchers report.

view more 

Credit: Sundharraman Subramanian and Alaina Pabbathi, Cryo-EM Core Facility, Michigan State University

Every 15 minutes, someone in the U.S. dies of a drug-resistant superbug. A few decades from now, antibiotic-resistant bacterial infections threaten to become the leading cause of death worldwide, outpacing cancer.

In the race for a solution to the antibiotic resistance crisis, a century-old practice is attracting renewed interest. The treatment, called phage therapy, involves co-opting friendly viruses that kill bacteria but ignore human cells.

Bacteria can — and do — develop resistance to phages, just as they do with antibiotics. But unlike antibiotics, phages can evolve counter defenses of their own.

Now, researchers at Michigan State University have identified a counter defense used by a group of phages common in the human gut, called Enterobacteria phage T2, that helps them stay one step ahead of their bacterial hosts.

These phages have mutation hotspots scattered throughout their genomes that help them modify key defense genes, the researchers report.

In a study published Aug. 13 in the journal Nature Microbiology, they show that these mutation hotspots help diversify their progeny to employ different survival strategies, ensuring that at least some continue to infect and kill no matter what countermeasures their bacterial hosts throw at them.

“They’re essentially hedging their bets,” said co-author Chris Waters, a core faculty member in MSU’s Ecology, Evolution, and Behavior program.

“If we can harness these kinds of evolutionary tricks, we might be able to make more effective phage therapies in response to the antibiotic resistance crisis,” Waters added.

The idea of using phages in medicine isn’t new. Cocktails of phages have been used since the 1920s to treat dysentery, sepsis, pneumonia and other ailments, particularly in France, Poland and parts of the former Soviet Union.

Interest in phage therapy waned in the West after the discovery of penicillin and other chemical antibiotics in the 1940s. But now, with deadly microbes from MRSA to tuberculosis becoming resistant to more and more of these drugs, researchers are revisiting phage therapy to combat antibiotic-resistant infections.

When phages invade, they latch onto a bacterium and inject their genes into the cell. Once inside, they hijack the bacterium’s internal machinery and turn it into a virus factory, forcing their host to churn out new phages until the cell bursts and releases them.

To fend off these attacks, bacteria have their own tactics. The researchers were studying one such strategy — a system in the bacterium that causes cholera — when they noticed something odd. In previous work, they identified a set of genes in cholera that spot the DNA of invading phages and chop it up before the phages can take over. But interestingly, this anti-virus protection didn’t last for long.

First author Jasper Gomez conducted the work while earning his Ph.D. in the Waters lab in MSU’s department of microbiology, genetics, & immunology.

In their experiments, the researchers transferred cholera DNA encoding the protective system to E. coli, a bacterium that is easier to work with in the lab, and exposed the bacteria to phages. Before long, the engineered E. coli were under attack. In other words, the phages quickly devised a workaround to bypass their hosts’ defenses, allowing them to sneak in and hijack their victims’ cells anyway.

“Within a few hours, the phages always started to win,” Waters said. “We couldn’t understand why,” he added.

The researchers sequenced the DNA of the resistant phages and found that many had “typos” in a gene called agt, particularly in a region of repetitive DNA where the same letter, or nucleotide base, appeared multiple times in the gene sequence.

“When I saw the data, I thought, oh my gosh,” Waters said. The region resembled a type of mutational hotspot called a contingency locus. Well studied in other organisms but never shown in phages before, such regions of the genome are known to be places where the cell’s DNA copying machinery sometimes “slips” and makes mistakes, Waters said.

The result is that, each time new phages are produced, they aren’t producing exact genetic copies of their ancestor. Some of the resistant mutants gain an extra repeat unit in the agt gene, while others lose one, throwing off how the gene’s instructions are read.

The researchers found that the repetitive region accumulates mutations thousands of times faster than the rest of the genome.

While mutations are often harmful, this changeability can give phages an evolutionary edge, Waters said. By continually churning out new mutants, they increase the odds that at least some will carry a mutation that lets them evade or disarm their host’s ever-changing arsenal.

“This changes our understanding of how phages evolve,” Waters said. “Instead of hijacking their hosts to mass produce exact copies of themselves, they are actually using these mutation hotspots to make a zoo.”

Phages outnumber bacteria by around ten to one, making them the most abundant organisms on the planet. The researchers focused on a type of phage that lurks in the gut, where it specializes on E. coli bacteria, but phages can be found just about anywhere, from the sands of the Sahara Desert to the ice of the Arctic Sea.

Working with MSU microbial evolution expert Jeffrey Barrick, the team found hundreds of similar mutation hotspots scattered across the genomes of other phage species as well.

Next, the researchers are looking into whether these mutation hotspots give phages an edge in other situations, such as adapting to survive and exploit their bacterial hosts after a shift in the environment, or evolving to infect new types of bacteria.

In much of the U.S., the U.K., and elsewhere, phage therapy is still far from mainstream; regulatory hurdles make it available only as a last resort. In the meantime, Waters and other researchers at MSU are exploring potential applications beyond the clinic, to treat bacterial infections in everything from honeybees and crops to pets and livestock.

“MSU could be a great phage therapy center for veterinary and agriculture applications,” Waters said.

“We’re never going to be able to completely get rid of resistance,” he added. “But if we can better understand how bacteria protect themselves from phage infection and how phages fight back, we might be able to minimize it.”

This research was supported by grants from the U.S. National Institutes of Health (GM139537, AI158433, GM088344 and F31AI186463) and the National Science Foundation (DEB-1813069 and DEB-1951307).

CITATION: "Phage-encoded contingency loci enable bet-hedging against host defence mechanisms," Jasper B. Gomez, Jeffrey E. Barrick, Christopher M. Waters. Nature Microbiology, Aug. 13, 2026. DOI: 10.1038/s41564-026-02445-w  

---

Journal

Nature Microbiology

DOI

10.1038/s41564-026-02445-w 

Method of Research

Experimental study

Subject of Research

Cells

Article Title

Phage-encoded contingency loci enable bet-hedging against host defence mechanisms

Article Publication Date

13-Aug-2026

 

Scientists create first AI-designed viruses to fight drug-resistant superbugs

Copyright AP Photo/Petr David Josek

By Marta Iraola Iribarren

Published on 07/08/2026 - EURONEWS

Researchers in the United States have used artificial intelligence to create viruses, opening pathways for new drug development and raising biosecurity fears.

Scientists are using a new form of generative artificial intelligence to design specialised viruses that can hunt and kill harmful bacteria. This breakthrough could lead to a new generation of antibiotics designed to defeat drug-resistant "superbugs".

Using the AI model Evo 2, which can create new DNA, scientists at Stanford University created a series of viruses known as bacteriophages – microorganisms able to kill bacteria.

In lab tests, a mixture of 16 “exceptionally good” viruses designed by Evo 2 was able to rapidly kill E. coli bacteria that were already immune to natural phages.

E.coli is a group of bacteria that can cause gut infections and is increasingly resistant to available antibiotics.

Antibiotic resistance is rising worldwide, driven mainly by the mis- and overuse of these kinds of antibiotics, which cause bacteria to develop ways to survive them, making current medicines useless.

“If the bacteria gain resistance to a single phage, it’s game over for the medication,” said Brian Hie, chemical engineer at Stanford and co-author of the study.

“But if you have multiple genetically distinct phages in a mixture, it would be harder for the bacteria to develop resistance to the entire cocktail.”

The researchers noted that this technology could be used in the future to target other harmful bacteria, such as those that cause tuberculosis, or a common hospital-acquired infection (MRSA).

Model available for everyone

The researchers have made the Evo 2 AI model openly and freely available for everyone to download and use, which has raised safety concerns.

The study authors acknowledged that making the tool open source has raised discussions about safety and that one primary concern is that "bad actors" could potentially use modified versions of the tool to design harmful biological agents.

“As the authors highlight, this raises some serious regulatory and safety concerns, to say the very least,” said Simon Clarke, associate professor in cellular microbiology at the University of Reading in the United Kingdom, who did not participate in the study.

“While work of this nature is normally tightly regulated, it is reassuring that these scientists have shown further restraint in providing important guardrails, but there is no guarantee that every other scientist attempting to do something similar will be so careful,” he added.

He argued that naturally occurring pathogens currently pose a greater risk than AI-designed ones, as they are already easier to access and produce than to create new ones from scratch.

According to the authors, an advantage of AI-designed biology over natural evolution is the ability to build safety checks directly into the process.

Related

• Experts warn open access bio-data could help AI design dangerous pathogens

The future of biology AI models

The model, Evo 2, was trained on millions of natural genomes from all across the world, allowing it to learn the complex "grammar" and rules that make a DNA sequence functional.

As with other biology AI models, this dataset includes biological data such as genetic sequences and pathogen characteristics

Currently, no universal framework regulates these datasets, and while some developers voluntarily exclude high-risk data, researchers argue that clear and consistent rules should apply to all.

In February 2025, Evo 2’s team announced that they had excluded pathogens infecting humans and other complex organisms from their datasets due to ethical and safety risks, and to “preempt the use of Evo for the development of bioweapons”.

Earlier this year, more than 100 researchers across the world wrote an open letter arguing that while open access to scientific data has accelerated discovery, a small subset of new biological data poses biosecurity risks if misused.

“The stakes of biological data governance are high, as AI models could help create severe biological threats,” the authors wrote.

The researchers said that striking the right balance between openness and necessary security restrictions on high-risk data will be essential as AI systems become more powerful and widely available.